The molecular mechanisms by which cytokines such as interleukin-1 or systemic hormones such as parathyroid hormone affect the osteoclast is unknown. Current data suggests that osteoclast activation is indirectly mediated, probably through a cell in the osteoblast lineage. In this project, we intend to identify the mechanisms by which the osteoclasts are stimulated by exposure to media harvested from stimulated cells with osteoblast characteristics. In preliminary data, we have found that stimulated osteoblasts release a macromolecular activity which stimulates osteoclast activity directly and stimulates bone resorption in organ culture assays. Our plan is to identify this activity and determine its role in the process of osteoclast activation. However, in addition to soluble factors, there appears to be an additional mechanism by which osteoclasts cause resorption of bone matrix by release of mineral. Recently, we have found that bone resorption processes are related to oxygen-derived free radical production, which appear to be associated with the formation of osteoclasts. We plan to determine the relationship between the osteoblast-derived factor, the formation of osteoclasts, and oxygen-derived free radical production. Understanding the complicated molecular mechanisms by which osteoclasts are activated in response to systemic hormones such as PTH and cytokines such as IL-1 appears essential for understanding the process of normal and pathological osteoclastic bone resorption.